Enantioselective chromatography and absolute configuration of N,N‐dimethyl‐3‐(naphthalen‐2‐yl)‐butan‐1‐amines: Potential sigma1 ligands

Abstract

We describe the preparation of racemic N,N-dimethyl-3-(naphthalen-2-yl)-butan-1-amines, potential sigma1 ligands, and their resolution via chiral HPLC. In order to obtain enantiopure compounds, direct chromatographic methods of separation using chiral stationary phases were investigated. Different methods suitable for both analytical and semipreparative purposes are proposed. The best resolutions were achieved using cellulose tris (3,5-dimethylphenyl carbamate) (Chiralcel OD and OD-H) and amylose tris (3,5-dimethylphenyl carbamate) (Chiralpak AD). On the basis of the preliminary chromatographic results, the resolution of compound 1 was transferred onto a Chiralcel OD semipreparative column. The enantiomers were obtained in high enantiomeric excess. The configurational assignment was performed by circular dichroism. Computational analysis was used to explore the enantioselective recognition process of compound 1 with the Chiralcel OD stationary phase.

Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists

“…36,37 Commercially available N -acetyl- S -(−)-alanine [ S -(−)-6 ], R -(−)-2 - phenylglycine [ R -(−)-7 ], and S -(−)-α-methylvaline [ S -(−)-9 ] were chosen as reference molecules, considering that the substituents at their stereogenic centers are similar to those of our compounds (highlighted in red in Figure 5). In fact, N -acetyl- S -(−)-alanine [ S -(−)-6 ], showing a similar sequence of groups/atoms, can be used as reference for (+)- 5a /(−)- 5a in CD analysis, and the results can be extended to the enantiomeric pairs (+)- 5b – e /(−)- 5b – e .…”

Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

“…Since the development of the first commercialized catalytic asymmetric synthesis of l ‐DOPA, enantioselective hydrogenation has played a relevant role in the preparation of chiral compounds, especially in industrial processes, and it is still one of the most reliable catalytic methods for the preparation of optically active molecules . Besides asymmetric synthesis, enantioselective HPLC resolution on CSPs has also been successfully employed for the isolation of enantiopure compounds, being a viable route for straightforward and rapid access to both enantiomers with high optical purity and yields . The determination of the absolute configuration of enantiopure compounds is then another unavoidable and complementary step to enantiopreparation, for which single‐crystal X‐ray diffraction is still considered the experimental technique of choice .…”

“…However, this technique presents some drawbacks, mainly related to sample characteristics (i.e., adequate resonant scattering properties and presence of heavy atoms), and the need of highly specific equipment . Electronic circular dichroism (ECD) and vibrational circular dichroism (VCD), as well as chemical correlation with a chiral compound of known configuration, have also been successfully applied to the absolute configurational assignment of biologically active molecules …”

Stereospecific effects of benzo[d]isothiazolyloxypropanolamine derivatives at β‐adrenoceptors: Synthesis, chiral resolution, and biological activity in vitro

“…Since an achiral molecule does not yield a CD signal, a CD detector can be used to distinguish enantiomers from achiral impurities. 8,9 As reported in Table 3, the online coupling of HPLC/ CD yielded directly the CD signal of the resolved peaks of compounds 2a and 2b. Figures 2 and 3 show the CD (upper) and UV (lower) chromatograms of the best chiral separation obtained with an HPLC/DAD/CD instrument.…”

“…In this article, we focus on the asymmetric synthesis and the direct chiral chromatographic separation of enantiomeric 2a-2b. On the basis of our previous experience on the chromatographic resolution of chiral compounds, 7,8 we used an isocratic normal-phase procedure with three polysaccharide-derived CSPs (Chiralpak AS-H and AD, Chiralcel OD-H) and various n-hexane-alcohol mixtures as mobile phases. We also used online coupling HPLC/CD for monitoring the purification of enantiomeric 2a-2b and to directly investigate their chiroptical properties.…”